Recent advances in neuroscience research have led to hypotheses that the etiology and treatment of different forms of human anxiety is related to alterations in brain noradrenergic (NA), "endogenous" benzodiazepine (BZ), and purinergic (PR) function. The proposed research will have the following specific aims (a) Assessment of central NA, BZ, and PR function in healthy subjects and patients with Agoraphobia and Panic Attacks (APA) and Generalized Anxiety Disorder (GAD) to allow determination of whether there is a dysfunction of these systems in anxiety disorders, and, more specifically whether different abnormalities exist in patients with APA and GAD. The specific hypothesis to be tested is that APA is primarily a disorder of NA function and GAD of BZ and/or PR function. (b) Investigation of the neurobiology of the panic attack in the APA patients. The specific hypothesis to be examined is that panic anxiety is associated with increased NA function. (c) Determination of the acute and chronic effects of structurally and therapeutically dissimilar antianxiety drugs on NA, BZ, and PR function and whether such effects are related to treatment response. The hypothesis is to be evaluated is that antipanic drugs decrease NA function and drugs effective for GAD primarily affect BZ and/or PR function. These aims will be accomplished by assessing NA, BZ, and PR function in the study groups prior to and during protocols involving double blind drug treatment, in vivo exposure to phobic stimuli, and individual and groups psychotherapy. Norepinephrine turnover will be measured by determination of plasma 3-methoxy-4-hydroxyphenelethylene glycol (MHPG) levels. The sensitivity of the alpha-2 adrenergic autoreceptor will be determined by measurement of the plasma MHPG, autonomic function and behavioral responses to yohimbine. Determination of the biochemical, behavioral, and autonomic effects of caffeine, a competitive inhibitor of BZ receptor binding and an adenosine receptor antagonist, will be used as an indirect measure of brain endogenous BZ and PR function. The studies described in this proposal should provide evidence whether functioning of the NA, BZ, and PR systems are abnormal in different types of anxiety states and whether the mechanism of antianxiety agents is related to effects on these systems. The information obtained from this study may be important for the development of more specific and efficacious treatment for patients with anxiety disorders.